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Home , Anaphylaxis, Arthus reaction, Hypersensitivity, Type II hypersensitivity, Type IV hypersensitivity

Timeline

• 1903 - Maurice Arthus

– Described a stereotypical response in rabbits following repeated intradermal injection of

– The response, characterized by Stephen Canfield, MD PhD local erythema, induration, Assistant Professor hemorrhage and Division of Pulmonary, became known as the “Arthus and Critical Care Medicine Reaction”

Timeline Timeline

• 1893 - Emil von Behring •1906 - Clemens von Pirquet and Bela Schick – Working with toxin noted that animals would suffer –Coined the term “” to describe strange systemic symptoms enhanced responses and even suffered by some patients weeks death following a second dose after receiving diphtheria or of toxin too small to injure anti-toxin horse serum normal untreated animals –Postulated for the first time that – Described this phenomenon as these hypersensitivity reactions might “hypersensitivity” be the product of immune response –Named these responses “allergic” from the Greek allos ergos, altered reactivity.

All historical photos from Silverstein, AM. 1989. A History of . Academic Press, San Diego

Timeline Definitions

•1902 - and Paul Portier •Hypersensitivity: –Set sail on the yacht of the Prince of –Broadest (Abbas) - Disorders caused by immune responses Monacco to study the effects of -Dysregulated response to foreign marine toxins in mammals ‣ ‣-Failure of tolerance to self-antigen –Attempted to protect dogs from the effects of toxins by innoculating them –Practical - Used clinically to refer to aberrant or excessive at low doses immune responses generated against foreign antigens, although the same immune processes apply in many autoimmune –Re-exposure to innocuous doses resulted in a rapid and •Allergy: suffocation –Symptoms elicited by encounter with foreign antigen in a –Coined the term “ana-phylaxis” to previously sensitized individual emphasize its antithesis to the familiar “prophylaxis”

1 Manifestations of Hypersensitivity Common to All Types •Symptoms frequently are localized to the anatomical site of antigen exposure: • Products of the adaptive Site of Exposure Syndrome Common Symptoms – Require at least one exposure for sensitization to occur

– Nasal Pruritis Sensitization can be long lived in the absence of re- Allergic Rhinorrhea exposure (>10 years) due to immunologic memory Congestion

Respiratory Mucosa

Bronchospasm Chronic Airway

Cramping Vomit/Diarrhea G.I. Mucosa Allergy

Manifestations of Hypersensitivity Type I (Immediate) Hypersensitivity

• Antigens: Site of Exposure Syndrome Common Allergens Symptoms – Classically exogenous, as opposed to “self” (autoimmune)

– Contact via mucous membranes and at low dose appears Contact Hives Urticaria Pruritis to favor type I sensitization

Skin • Reactions:

– Occur within seconds-minutes of exposure Contact Pruritis – Severity ranges from irritating to fatal • Immune Effect Hives/ Abd. Cramping – Blood Systemic Allergy Initial antigen contact leads to IgE production – On re-exposure, antigen-specific IgE initiates the reaction

Hypersensitivity: Gell & Coombs Classification IgE Production

•Occurs as part of a secondary immune response (generally multiple or persistent exposures) •Class switch to IgE is directed by IL-4 and IL-13 (Th2 ), and requires help (CD40L) •The propensity to make an IgE response to environmental antigens varies among individuals •“Atopic” individuals are those genetically predisposed to form IgE responses. That is, is heritable

Immunobiology (Janeway), 6th Ed.

2 Genetics of Atopy Allergy: Sensitization Phase

•Complex, multigenic heritability. Candidate genes: • Serum IgE produced by plasma cells has a short –Chrom. 11q - β-subunit of the high affinity FcεRI Τ1/2 (serum Τ1/2 IgG≈30 days; for IgE≈2 days) –Chrom. 5q - cluster: IL-3, IL-4, IL-5, IL-9, IL-13 • Rapidly taken up by FcεRI on tissue mast cells –TIM (T-cell, Ig domain, Mucin domain) - surface and circulating –protein, variation assoc. with IL-4/IL-13 prod.

–IL-12 p40 subunit (assoc. with asthma and AD) IgE •Variation in IgE response to specific allergens is associated with MHC II genetics

–DRB1*1501 is associated with IgE responses to specific pollen proteins

Allergy Epidemic Allergy: Effector Phase

• , including asthma and •Early Phase Response: within seconds-minutes , have been increasing in prevalence in –IgE crosslinking by antigen ¿ release of preformed mediators the economically “advantaged” parts of the world for 30 years – ¿ constriction, mucous secretion, ↑vascular permeability, ↑GI motility, sens. nerve stimulation –The “hygiene hypothesis” attributes increased allergic disease rates to generally decreasing microbial exposure in early life which would normally provide a Th1-promoting effect IgE ‣-Neonatal bias: ↓IL-12 (DC) and ↓IFN-γ (T cells) ‣-Birth order: ↓allergy rates among 3rd- and 4th-born children ‣-Protective effect of day care ‣-1990 - East/West Berlin immediately after the wall fell: East had ‣-↓ rates, ↑prev. childhood infection, but ↓’ed asthma ‣-Hx of measles or HAV infection, or +PPD ¿↓allergy rates

Allergy Epidemic Allergy: Effector Phase

•Weighing against the Hygiene Hypothesis: •Early Phase Response: within seconds-minutes

–Despite this epidemiologic data, some evidence is hard to –IgE crosslinking by antigen ¿ release of preformed mediators reconcile –histamine ¿ smooth muscle constriction, mucous secretion, ↑vascular ‣-Previous infection with helminths, which generates a strong Th2 permeability, ↑GI motility, sens. nerve stimulation response, is also associated with protection against allergy

‣-Early life exposure to pathogens is also associated with decreased Allergen risk of (e.g., type I diabetes), a classic Th1- mediated condition IgE

–Revised hygiene hypothesis - early life exposure to microbial pathogens influences the balance of immune responsive vs. immune modulating influences

3 Allergy: Effector Phase FcεRI Signaling

•Structure: •Early Phase Response: within seconds-minutes –Alpha, Beta, Gamma-Gamma –IgE crosslinking by antigen ¿ release of preformed mediators •Alpha - binds IgE monomer –histamine ¿ smooth muscle constriction, mucous secretion, ↑vascular •Beta, Gamma - signal permeability, ↑GI motility, sens. nerve stimulation •ITAM’s Allergen –Conserved sequences within the IgE tail containing tyrosines

–ITAM Tyr is phosphorylated on ligand binding

Immediate –Serve as docking sites for downstream Histamine Proteases Hours activating kinases Minutes Cytokines: Prostaglandins IL-4, IL-13

Allergy: Effector Phase

• Innate responder cell in Type I hypersensitivity •Late Phase Response: 6-24 hours after exposure – Production in marrow induced by IL-3, IL-5, GM-CSF – production of newly synthesized mediators – Chemotax to tissue sites: IL-5, Eotaxin-1, 2, 3 ‣-Leukotrienes ¿ smooth mm. contraction, vasodil., chemotaxis ‣-Cytokines ¿ recruitment of PMN and eosinophils – “Primed” by IL-5, eotaxins, C5a ‣ -↑FcγR and C’ receptor expression ‣ -induce FcεR expression Allergen ‣ -↓threshold for IgE – On activation, eosinophils secrete

‣ -Toxic proteins- major basic protein, eos. cationic ‣ -protein, eos. derived neurotoxin Immediate Histamine ‣ -IL-3, IL-5, GM-CSF, IL-8 Proteases Hours Heparin Minutes Cytokines: ‣ -LT’s Prostaglandins IL-4, IL-13 Leukotrienes

Evolutionary Role of Type I Mast Cell Degranulation Response

Pre-exposure to Ag Post-exposure to Ag • Mast cells line all subepithelial mucosa

– Rapid recruitment of PMN, eosinophils, to sites of pathogen entry

– ↑Lymph flow from peripheral sites to lymph node

– ↑G.I. motility ¿ favors expulsion of G.I. pathogens • Important role in parasite clearance –/– – c-kit mice have no mast cells ¿↑susceptibility to trichinella, strongyloides

– depletion (Ab-mediated) ¿↑severity of schistosomal infection

4 Evolutionary Role of Type I Anaphylaxis Response

•STAT6: •Response to systemic circulation of allergen –Mediates IL-4/IL-13 signaling –Triggering of mast cells in peri-vascular tissue –Required for IgE class switch –Circulating histamine, PG’s/LT’s ¿ vascular leak, vasodilatation –STAT6–/– mice have no IgE –High-output shock (increased cardiac output, ↓↓BP) •Wild type or STAT6–/– mice –Other symptoms: urticaria, , , laryngeal edema with were injected with 500 N. airway compromise, G.I. cramping, diarrhea brasiliensis larvae •Rapid progression over seconds-minutes •Treatment - •Worm counts and fecal egg counts were assessed at 13 –early administration I.M., followed by (H1 and H2 blockade) ¿ treat early phase days –subsequent administration ¿prevent late phase

Urban, et al. (1998) . 8:255

Type II Hypersensitivity: Type I Sensitivity in Allergy (Ab) Mediated

• Target-specific IgM and IgG mediate damage •Type I Hypersensitivity mediates: • Targets: – Allergic Rhinitis/conjunctivitis (Hayfever) – Self-molecules altered by foreign antigen ¿ neo- – Asthma ‣ - conjugates to RBC surface proteins ¿ new – Food/ reactions penicilloated-protein serves as a target for IgM/IgG ¿ – Contact urticaria intravascular hemolysis

– Some forms of eczema – Self-molecules unaltered = breaking of tolerance

– Anaphylaxis - food, sting, drug, exercise-induced ‣ -Group A Strep pharyngitis yields Ab’s to the Strep M protein ¿ Ab’s cross react with cardiac muscle and valves ¿ scarring

Type II Hypersensitivity: Ab Type I Sensitivity in Allergy Functions •The mechanisms of type II hypersensitivity are exactly •Documenting allergic sensitivity: skin testing the those of normal Ab function, plus some:

–Allergenic extract (airborne, food, ) is introduced by prick Ab Function Target Result or injection intracutaneously Splenic clearance, Opsonization Platelet surface proteins –Sensitization is evident within 15-20 minutes as a wheal/flare at the allergen introduction site Neutralization Acetylcholine receptor

Glomerular basement membrane ADCC Goodpasteur’s Disease proteins

C’ Fixation Penicilloyl-RBC protein conjugates Hemolytic anemia

Non-Physiologic TSH receptor Grave’s Disease

5 Type III Hypersensitivity: Type III Hypersensitivity: Mediated Immune Complex Mediated •First Description: •Serum Sickness: Systemic Arthus-like reaction

–(Arthus, N.M. 1903. Injections repetees de serum de cheval chez la lapin. C.R. –(Pirquet, C., von and B. Schick. 1905. Serum sickness. Franz Denticke, Soc. Biol. (Paris) 55:817-820) Leipzig)

–Rabbit received horse serum containing anti-toxin antibody ‣ -Rash, fever, lymphadenopathy and arthralgias in recipients of anti-diphtheria antisera made in horses (hint: 2-3 weeks post-infusion)

•Rabbit Model (Dixon and Lambert, 1960’s):

‣-Injection of radiolabeled bovine serum albumin (BSA) day zero

‣-Serum BSA and anti-BSA antibody levels were tracked

‣-Look for serum immune complexes and proteinuria

–After several days, antigen (toxin) was injected subcutaneously

–Classic Arthus reaction occurs within 5-8 hours:

‣-Local erythema/tenderness with edema, necrosis, hemorrhage

Arthus Reaction Importance of C5a in I.C. Disease

•Immune Mechanism •Mouse Model of Immune Complex Disease:

–Antibody-Antigen complexes form within blood vessel walls –Infuse Anti-ovalbumin Ab via trachea; ovalbumin via I.V.

–Complement fixation generates C5a –I.C.’s form at respiratory capillaries examine histology at 4 hours ‣- chemoattractant ¿ PMN infiltration ‣- - local mast cell histamine release ¿ tissue edema

–Neutrophil activation by FcγR’s ¿ release of cytotoxic enzymes

–Platelet aggregation by FcγR’s ¿ small vessel thrombosis, necrosis

–Local release of IL-1, TNF-α, and IL-8 - propagation

Intratracheal Anti-Ova Ab ++ +

I.V. Ova –+ +

Genotype C5aR+/+ C5aR–/–

Bozic, et al. (1996) Science. 273:1722

Immune Complex Formation Importance of FcγR’s in I.C. Disease

• B/W Mouse - spontaneous accumulation of I.C.’s in the Antibody-Antigen Equivalence glomerulus

•FcγRI and FcγRIII - contain ITAM’s; activating for

Serum #1 • γ-chain knockout (γ–/–): Lacks expression of FcγRI and FcγRIII

Serum #2 Antigen

Serum #3 Precipitation Increasing Antigen

Clynes, et al. (1998) Science. 279:1052

6 Immunology Wars Delayed Type Hypersensitivity

•Epic Immunologic Battle: 1870-1950 • Group of related responses to antigen, all – “Humoralists” (France): Hypersensitivity is mediated by serum dependent on cell-mediated immunity factors • Although prior sensitization is required, – vs. reactions occur over 1-3 days following re- – “Cellularists” (Germany): Hypersensitivity is mediated by phagocytes exposure •By 1915, the Humoralists appeared to have won • T cells: necessary and sufficient to elicit the

– Hay fever, asthma, anaphylaxis reaction

– Drug-induced hemolysis transferrable with serum – Athymic subjects (animal or human) are not sensitizable

– Arthus reaction, serum sickness – T cell depletion (via anti-T cell Ab’s) reverses sensitization

– Transfer of purified T cells confers sensitization

Type IV Hypersensitivity: Varieties of DTH Reactions Tuberculin Reaction •1892 - Robert Koch

Reaction Clinical Site/ –Discoverer of tubercle bacillus Type Histology Time Appearance Antigen –Attempted to prevent TB by inoculation with bacillus extract 48-72 T cells followed by Epidermal: organic Contact Eczema , edema of the mols., poison ivy, –Unfortunately: hours epidermis heavy metals

‣-No protection for naive individ.

‣-Reactivated disease in exposed T cells, monocytes, Intradermal: 48-72 Local Tuberculin macrophages, basophils PPD, candida, hours Induration –But: intradermal injection of bacillus fibrin deposition/edema mumps extract in previously exposed individuals resulted in a stereotypic indurated lesion Skin, viscera: 21-28 Hardened Macrophages, epithelioid within 48-72 hours persistent Ag (TB, giant cells, fibrosis days Nodular )

Type IV Hypersensitivity: Delayed Type Common to all DTH Reactions

• 1942 - Karl Landsteiner and Merrill Chase •Histology of the DTH reaction: –T Cells - CD4 (Th1); some forms CD8 – Demonstrated transfer of –Macrophages/monocytes tuberculin test sensitivity in –Basophils guinea pigs –Fibrin – Sensitivity is transferred from –If persistent antigen: multinucleated giant cells; granulomata TB-exposed to unexposed animals with leukocyte transfer, •Cytokines found at the site of a DTH reaction: but not with serum transfer –IL-2

– Redemption for the Cellularists –IFN-γ –TNF-α

–Macrophage chemotactic protein (CCL-2)

7 Penicillin Mediates All Types of Contact Sensitivity: DTH Hypersensitivity •Phase One: Initial Exposure - Sensitization •Immune-mediated adverse reactions occur at –Hapten - small organic molecule, frequently lipophilic crossing a rate of 1 per 100 administrations epidermal barrier by diffusion, associates with cell proteins

‣-Chromates (leather tanning), (poison ivy), nickel

–Haptenylated proteins are taken up by Langerhans’ cells - peptides Type Mechanism Example bearing hapten are loaded onto MHC I and MHC II

–LC’s migrate to regional lymph nodes, activate naive T cells I IgE-mediated Acute anaphylaxis, urticaria

C’-mediated cytolysis Hemolytic anemia II Opsonization Thrombocytopenia

Serum sickness III Immune Complex Damage Drug fever,

IV T Cell mediated Contact sensitivity

Contact Sensitivity: Hapten DTH

• Phase Two: Re-exposure - Elicitation

– Hapten-specific memory T cells bearing the cutaneous lymphocyte antigen (CLA-1) continuously migrate between lymphatics and skin

– Re-encounter with haptenylated protein may occur on:

‣ -Langerhans’ cell (MHC II) ¿ Th1 cell secretion of IFN-γ, MCP-1 with macrophage recruitment

‣ -Keratinocyte (MHC I) (lipophilic hapten) ¿ CD8 CTL activation ¿ release of perforins and granzyme ¿ local tissue damage

Hypersensitivity Progression

• Antigen-specific responses may progress from one type of hypersensitivity to another:

– allergy among healthcare workers

‣ -Initial reaction is typically a contact sensitivity (type IV reaction)

‣ -With recurrent latex contact, sensitivity progresses to latex-specific IgE, imparting risk of anaphylaxis

– p-aminobenzoic acid (PABA), the active ingredient in many sunscreens, can act as a contact sensitizer

‣ -PABA DTH reactivity is associated with ↑’ed risk of immediate type hypersensitivity to local anesthetics (e.g., ) due to cross-reactivity of the aromatic core

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